A widely held view of autoimmune disease is that pathogenesis and disease result primarily from an imbalance in the immune system, characterized by a failure to regulate immunological pathways, particularly those causing tissue destruction. The non-obese diabetic (NOD) mouse spontaneously develops autoimmune IDDM and is known to have a number of immunoregulatory defects. The first aim of this proposal is to further delineate these defects or imbalances through the analysis of specific immunoregulatory functions (antigen presentation, expression of adhesion molecules, cytokine and chemokine production) in diabetes-resistant. Under the second aim of this project, the contribution of Th1 and Th2 T cells to immunoregulation will be investigated. Although it has been shown by others that increasing levels of cytokines made by regulatory Th2 T cells can lead to delay or inhibition of disease in the NOD mouse, there has been no convincing demonstration that Th2 T cells mediate prevention. The applicant is producing Th2 T cell lines and clones from NOD mice and from diabetes-resistant NOD congenic mice to determine whether protective Th2 T cells can be isolated and if so, what constitutes a protective phenotype. The results from these studies should provide a clearer understanding of factors that contribute to autoimmune diabetes and whether correction of specific immunological dysfunction will result in prevention or amelioration of disease.